**4. Diagnosis**

The approach to diagnosis of NPSLE remains challenging as clinicians need to be thorough when it comes to history taking, physical examination and other methodologies including serologic examination, imaging and medical procedures (e.g. lumbar puncture) that can facilitate accurate diagnosis. Primarily, the arduous task begins with identifying whether the manifestations are secondary to the disease activity or not. These steps and processes will help in identifying the pathogenetic pathway involved and the proper course of management at the end (**Figure 1**).

Based on the presentation of the neuropsychiatric signs and symptoms, the assessment process should be tailored-fit accordingly. Likewise, localizing the areas of the CNS involved also has its limitations. In example, the focal neurologic symptoms correlate well with the conventional magnetic resonance imaging (MRI) but abnormalities associated with altered perfusion or neurometabolite changes can be best demonstrated by functional imaging techniques [4]. However, more than half of patients diagnosed with NPSLE have a normal MRI of the brain [18]. Single photon emission computed tomography (SPECT) provides an estimate of regional cerebral blood flow and thought to be more sensitive than MRI for the evaluation of NPSLE. But studies were inconsistent [19].

Computerized tomography (CT) is being used to exclude focal abnormalities such as hemorrhage, infarcts, tumors, cortical atrophy and calcifications. On the other hand, metabolic neuroimaging such as positron emission tomography/PET,

#### **Figure 1.** *NPSLE in kaleidoscope. NPSLE in summary featuring the basic diagnostic approach and management.*

#### *Literature Review on Neuropsychiatric Lupus DOI: http://dx.doi.org/10.5772/intechopen.106955*

MR spectroscopy) and perfusion imaging such as single photon emission computer tomography/SPECT) can detect abnormalities in patients with psychiatric manifestations but otherwise have normal MRI studies [4]. Functional MRI (fMRI) also is being used to assess for cognitive function in SLE.

CSF analysis is utilized in cases of ruling-out infection. Likewise, it becomes as important in some cases such as aseptic meningitis, transverse myelitis and vasculitis.

Biomarkers are also used to better screen and monitor treatment for NPSLE. At present, the autoantibodies used in the diagnosis and therapeutic decisions include antineuronal, anti-ribosomal P, and anti-NR2 antibodies. Meanwhile, other than autoantibodies, chemokines and cytokines, intra-thecal levels of PAI-1 and MMP-9 are used for screening & monitoring purposes.

Magro-Checa et al. proposed a diagnostic approach based on the clinical presentation of patients with NPSLE manifestations. This consisted of matched diagnosis and work-up, procedure or imaging to be done. On the other hand, there have been attribution models proposed in order to strengthen the diagnosis. These were developed very carefully and limitations were also determined accordingly [17].

In an international inception cohort study Hanly et al. described an attribution model in which the level of stringency was based on three simple rules that take into account the temporal relationship between the neuropsychiatric (NP) event and the diagnosis of SLE, the type of NP event and a comprehensive list of exclusions or associations according to the American College of Rheumatology (ACR) nomenclature. In this study, they concluded that 28% of SLE patients experienced at least 1 NP event around the time of diagnosis of SLE, of which only a minority were attributed to SLE [20].

Bortoluzzi et al. developed a new algorithm for attribution of neuropsychiatric events in SLE in 2015. This enabled identification of which NP events have a high probability of being or not being attributed to the disease among SLE patients in a more standardized and reproducible manner. When compared with expert clinical judgment, it demonstrated a good performance in sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) with a confident assumption of correctness at 33%. However, this was not intended as a substitute for clinical judgment which remains as the cornerstone of the diagnosis and management of NPSLE [21].

Magro-Checa et al. in 2017 provided a prospective date from the Leiden NPSLE cohort and determined the value of multidisciplinary reassessment in attribution of neuropsychiatric events to SLE. This model has showed that each NP event was attributed to one of the following groups: NPSLE or NP events directly related to SLE, undefined NPSLE, and non-NPSLE or NP events better explained by other etiology. Non-NSPLE events were divided further into subgroups: due to primary NP disease, due to medication or drugs, due to a complication of SLE and due to other concomitant disease. This model showed reassessment of NP symptoms in SLE and re-classified a total of 13.8% of NP events. Furthermore, the percentage of NP events attributed to SLE was 31.3% [22].

Individualizing the approach to each patient presenting with NPSLE is also applicable since there is no gold standard in the approach to diagnosis. The complexity of the signs and symptoms necessitate a diagnostic algorithm applicable for the most number of cases.

### **5. Treatment**

Besides the general treatment which includes control or correction of aggravating factors, nonpharmacological interventions and symptomatic therapy for the different syndromes associated with NPSLE, the approach also depends on which pathway is primarily involved. Govoni et al. had illustrated the current treatments on NPSLE. In this study, it had been emphasized that the identification of the most likely cause and contributing factors to the NP event is determined by careful assessment and utility of diagnostic tests that are deemed appropriate. Similarly, it is important to determine whether the disease activity is reversible or irreversible by treatment as this can provide the framework for the appropriate modality in each patient [8].

Magro et al. provided a detailed review on the therapeutic strategies in NPSLE from the general treatment to therapies specific for the pathway that is involved (ischemic vs. inflammatory). In this perspective, it is pointed out that a combination of immunosuppressive therapy and secondary prevention may be used in the same patient when both ischemic and inflammatory pathogenic mechanisms are suspected [22].

In clinical practice, therapy will be directed at inflammation or at prevention of ischemic events upon confirmation of the most likely process involved. Psychotherapy had a beneficial effect on anxiety, depression and quality of life in a controlled clinical trial in 80 SLE patients [23]. Positive outcome with antidepressants had been reported in some observational studies [24]. The use of antiseizure drugs in SLE has also not been subjected to controlled clinical trials while antipsychotic medications are used in the majority of patients with lupus psychosis [25, 26]. Among medications used for generalized seizures include barbiturates and phenytoin while for partial complex seizures may include clonazepam, valproic acid and carbamazepine. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used for pain relief such as headache [22]. Systematic studies in SLE patients are lacking focusing on behavioral rehabilitation of cognitive dysfunction [8].

The presence of aPL antibodies predisposes to the development of thrombotic events such as stroke and prior ischemic events. Primary prevention in APS does not support the use of low-dose of aspirin or warfarin according to current evidence and still necessitates large and well-designed clinical trials [27]. SLE patients with focal manifestations attributed to aPL antibodies requires lifelong anticoagulation [28]. Warfarin is used in the prevention of recurrent thrombosis. Other adjunctive therapies of use are antimalarials including hydroxychloroquine, statins, and antiplatelet agents. Antimalarials exert beneficial effects both as anti-inflammatory and antithrombotic.

In NPSLE patients, the use of glucocorticoids is based on clinical experience. Methylprednisolone pulse therapy consisting of 1 g intravenously for three consecutive days followed by tapering doses of oral prednisolone depending on the severity of NPSLE manifestation is a usual practice. This is acknowledging that the mechanism responsible is inflammatory in nature similar to when other organ systems are affected during lupus flares. Positive effects of cyclophosphamide treatment had been described in several case series [29, 30]. One retrospective study involving 31 NPSLE patients suggested benefit from glucocorticoid use and monthly intravenous cyclophosphamide (250–1000 mg/m2 ) [31]. Furthermore, Stojanovich et al. concluded in a study involving 60 NPSLE patients that patients treated with cyclophosphamide showed more clinical and eletrophysiological improvement on cerebral function [32].

Due to mild side effects, azathioprine is frequently used for maintenance therapy or as a steroid-sparing agent. There are very few data on the effects of azathioprine in NPSLE. In a study by Ginzler et al. including 68 SLE patients with poor prognosis due to renal or NP events, 54 patients treated with azathioprine had improved significantly on long-term survival and fewer hospitalization. In clinical practice, similar

*Literature Review on Neuropsychiatric Lupus DOI: http://dx.doi.org/10.5772/intechopen.106955*

with previous medications, although not yet supported by current evidence, azathioprine is widely used as maintenance therapy after cyclophosphamide in patients with severe NSPLE manifestations and even as an option in mild NPSLE [33].

The effect of mycophenolate mofetil in NPSLE patients is described in very few cases and not conclusive. Similarly, the use of methotrexate is very rarely use in NPSLE and evidence is limited to several case series via intrathecal route. Meanwhile, the efficacy of plasma exchange or cyclosporin A remains unknown because of concomitant use [34].

The effect of biologic therapies remains limited including rituximab, belimumab, and anifrolumab. The use of rituximab alone or in combination with other immunosuppressives like cyclophosphamide have reported positive effects but needed more studies [35–37].
